ClinVar Miner

Submissions for variant NM_002528.7(NTHL1):c.244C>T (p.Gln82Ter) (rs150766139)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000657657 SCV000705556 uncertain significance not provided 2017-01-13 criteria provided, single submitter clinical testing
GeneDx RCV000657657 SCV000779405 pathogenic not provided 2019-01-04 criteria provided, single submitter clinical testing This pathogenic variant is denoted NTHL1 c.268C>T at the cDNA level and p.Gln90Ter (Q90X) at the protein level. The substitution creates a nonsense variant, which changes a Glycine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been observed in several individuals with colorectal cancer and/or adenomas (Dallosso 2008, Rivera 2015, Timofeeva 2015, Weren 2015). Weren et al. (2015) identified NTHL1 Gln90Ter in the homozygous state in 7 individuals from three families with a history of multiple colorectal adenomas and/or colorectal cancer. Additionally, Rivera et al. (2015) identified NTHL1 Gln90Ter in the compound heterozygous state with a canonical splice variant, confirmed to be in trans through familial testing, in an individual with colon cancer, multiple colorectal adenomas, and other neoplasms. Lastly, other studies identified NTHL1 Gln90Ter in the homozygous or compound heterozygous state in several unrelated individuals with colorectal adenomas and colorectal cancer (Chubb 2016, Belhadj 2017, Broderick 2017). Based on currently available information, we consider NTHL1 Gln90Ter to be pathogenic. Of note, NTHL1-Associated Polyposis (NAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in NTHL1. Although this variant is considered pathogenic, a second pathogenic variant, as would be required for expression of the recessive condition NAP, was not detected in this individual. We cannot exclude the possibility that this patient harbors a second disease-causing NTHL1 pathogenic variant that is undetectable by this test. NTHL1 has only recently been described in association with cancer predisposition and the risks are not well understood. Based on available data, the presence of two pathogenic variants in NTHL1 is indicative of NTHL1-Associated Polyposis (NAP), an autosomal recessive condition that may confer an increased risk for colorectal cancer and polyps. Although the development of colorectal cancer and attenuated polyposis appears to be the predominant feature of NAP, multiple case reports have described individuals with NAP to have developed multiple extracolonic neoplasms, including breast, endometrial, bladder, and skin cancers as well as several benign findings (Rivera 2015, Weren 2015, Belhadj 2017). The National Comprehensive Cancer Network has management guidelines for individuals with two pathogenic variants in NTHL1 (NCCN).
Invitae RCV000657657 SCV000957470 pathogenic not provided 2019-01-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln90*) in the NTHL1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs150766139, ExAC 0.4%). This variant has been observed as homozygous, and on the opposite chromosome (in trans) from a likely pathogenic variant, in many individuals affected with multiple adenomatous polyps and often colorectal cancer (PMID: 25938944, 27720914, 26559593). These findings are consistent with autosomal recessive inheritance, and suggest that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 192319). Experimental studies have shown that deletion of the N-terminal 92 amino acids of the NTHL1 protein results in complete loss of its activity (PMID: 12144783). Loss-of-function variants in NTHL1 are known to be pathogenic (PMID: 25938944, 26559593). For these reasons, this variant has been classified as Pathogenic.
Academic Department of Medical Genetics, University of Cambridge RCV000850062 SCV000992218 pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
OMIM RCV000172911 SCV000223893 pathogenic Familial adenomatous polyposis 3 2015-06-01 no assertion criteria provided literature only

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